The proposal's short-term aim is to eludicate the molecular basis for the action of resistant variants of Human Immunodeficiency Virus 1 (HIV-1) protease by comparing the structures and activities of selected mutants of HIV-1 and Rous sarcoma virus proteases. The specificity studies proposed will be: 1) to cover a broader set of oligopeptide substrates in order to more fully characterize the inhibitor-resistant HIV-1 protease mutants; and 2) promote new studies on the molecular basis for the specificity of the related human T-cell leukemia virus type 1 (HTLV-1) protease. The long-term aim is to predict new protease inhibitors and therapeutic strategies to overcome the problem of drug-resistance.